University of California, San Francisco (UCSF)

The MANF Signaling Pathway as a Novel Therapeutic Target for Parkinson's Disease

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder (after Alzheimer’s) associated with aging and affects estimated 1.5% people worldwide over 65 years of age. PD develops because of progressive degeneration and loss of dopaminergic neurons during aging. Current therapeutic interventions for PD only partially alleviate symptoms and do not restore normal dopaminergic neuron functions or prevent progressive neurodegeneration. Identifying novel molecular targets and searching for therapeutic agents that block dopaminergic neuron degeneration and promote their restoration is a key challenge in the field. Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is a recently discovered protein that exhibits remarkable beneficial effects on dopaminergic neurons, including protection against degeneration and promoting neurorestoration of mammalian PD models. However, molecular mechanisms of MANF actions are still largely unknown. In this project we seek to identify novel components of the MANF signaling transduction pathway. We take advantage of the powerful genetics of C. elegans to address several fundamental questions regarding the MANF signaling pathway. The manf gene is evolutionarily conserved in both vertebrate and invertebrate animals and, in contrast to other model systems with inactivated manf gene, the C. elegans manf-1mutants are viable.Using C. elegans to study MANF signaling establishes a new research paradigm and might become a turning point in the MANF research. We anticipate identifying the major conserved components and regulators of the MANF signaling pathway that should become novel therapeutic targets for the treatment of the Parkinson‘s disease and other degenerative diseases associated with aging.